Review
Mechanisms and abuse liability of the anti-histamine dimenhydrinate

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Abstract

The over-the-counter anti-emetic dimenhydrinate (DMH) (Gravol or Dramamine) has been reported to be abused for non-medicinal purposes. Street drug users abuse DMH for the acute effects of euphoric sensations and hallucinations, while psychiatric patients abuse DMH for its anxiolytic or anti-cholinergic effects. DMH is an H1 histamine receptor antagonist, but it interacts either directly or indirectly with other neurotransimitter systems, including those using acetylcholine, serotonin, norepinephrine, dopamine, opioids or adenosine. Animal behavioural studies, such as self-administration, conditioned place preference, drug discrimination, and modulation of operant responding, show that anti-histamines have abuse potential. Further support comes from reports of acute and chronic abuse of DMH by humans. Collectively, results confirm the abuse liability of DMH.

Introduction

Over-the-counter (OTC) drugs are not always used for their intended purposes. Thus, anti-histamines may be administered for their reinforcing rather than their analphylactic effects. For example, heroin addicts will mix the narcotic analgesic pentazocine with the anti-histamine tripelennamine, a concoction known on the street as ‘T's and Blues’. This drug combination creates a ‘rush’ that is indistinguishable from heroin [45]. Users of hallucinogens, such as lysergic acid diethylamide (LSD), or marijuana will substitute these drugs with large doses of OTC anti-histamines to achieve euphoric tactile, visual or auditory sensations [4], [26]. These examples show that anti-histamines have abuse potential.

In recent years, a number of case study reports indicate that dimenhydrinate (DMH), an OTC anti-histamine with the trade name Gravol or Dramamine, has abuse potential. DMH is composed of the anti-histaminergic agent diphenhydramine (DP), sold under the trade name Benadryl, plus the methylxanthine, 8-chlorotheophylline, in equimolar ratios [18], [20]. At recommended doses DMH is used most commonly as an anti-emetic, an effect that is attributed generally to it's antagonism at the H1 receptor [23], [55]. Both acute and chronic abuse of DMH have been reported.

In 1997, a series of case studies described DMH abuse by adolescents who administered the drug for its hallucinogenic and euphoric properties [41]. In large doses (more than four times the recommended dose), DMH produces a ‘high’ characterised by hallucinations, excitement, incoordination, and disorientation [2], [4], [9], [18], [26]. These cases of DMH abuse have been reported in individuals with a history of illicit drug use [4], [26], [41].

Individuals with a history of a psychiatric disorder, such as schizophrenia [2], depression, substance abuse, and personality disorders [9], [18], [35] may repeatedly administer DMH. In such cases, tolerance to the acute subjective effects of the drug and symptoms of drug withdrawal can occur. Chronic consumption of DMH may be difficult to identify because symptoms of the dependence resemble the symptoms of some psychiatric disorders such as major depression and dysthymia [18].

Many researchers suggest that DP, the anti-histaminergic component of DMH, is responsible for the reinforcing effect of the drug [27]. This anti-histamine influences neurotransmitter systems either directly, by acting on receptors or transporters, or indirectly, by modulating their influence. The neurotransmitter systems that have been implicated in the behavioural effects of DMH include those using dopamine [53], acetylcholine [9], serotonin [8], norepinephrine [22] and opioids [51]. The neural mechanisms underlying the abuse potential of DMH are not yet established, however, and evidence for the abuse potential of DMH in particular, and of anti-histamines in general, underscores the need to identify these mechanisms.

Section snippets

Dimenhydrinate

The effectiveness of DMH as an anti-emetic was first reported in 1949, when it was found to aid in the prevention of both seasickness [19] and airsickness [50]. The anti-emetic properties of DMH are thought to be produced by antagonism of H1 histamine receptors in the vestibular system [23], [46], [55]. For example, electrophysiological studies have shown that both DMH and DP can suppress vestibular neuronal firing that is enhanced by angular or linear acceleration motions [23]. This would

Animal studies

Animal experiments provide researchers with a method of assessing abuse liability of drugs in controlled settings. To our knowledge, DMH itself has not been examined in these studies (except in our own recent and as yet unpublished work, see below), although a number of behavioural paradigms have been used to evaluate the reinforcing effect of the components of DMH, i.e., the anti-histamine DP and the methylxanthine 8-chlorotheophylline. These include drug self-administration, conditioned place

Conclusions

This review emphasizes the abuse potential of anti-histamines, and in particular DMH and DP; anti-histamines are reinforcing in animal paradigms, and humans report desirable subjective effects following the drugs' administration. Animal studies describe the ability of anti-histamines, and particularly DP, to produce reinforcing effects and to potentiate the reinforcing effect of other abused drugs. These studies also describe how administration of anti-histamines, such as DP, produces effects

Acknowledgements

The authors wish to thank Drs Ronald Black and Khem Jhamandas for their valuable comments on an earlier draft of this paper. The work was funded by grants from the Natural Sciences and Engineering Research Council of Canada to RJB and MCO.

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